This invention relates to new iron chelators which are useful in the treatment of acute iron overload disorders, such as, iron poisoning, hemocheomotosis and transfusional hemosiderosis resulting from frequent blood transfusions during the treatment of .beta.-thalassemia otherwise known as Cooley's Anemia, sickle cell anemia, aplastic anemia and some forms of leukemia. More specifically, the present invention contemplates synthetic polymeric iron chelators which are based upon hydroxamic acids having the following general formula: ##STR2##
Hydroxamic acids have long been known for their powerful ability to selectively bind iron, Fe(III). Microorganisms have incorporated hydroxamic acids into complex organic molecules for the purpose of scavenging iron from the environment. Since about 1960, desferrioxamine-B (DFB) one of these naturally occurring tris-hydroxamic acids, has been used in medicine to sequester and remove iron from patients with iron overload arising from causes such as iron poisoning and Cooley's Anemia and today many varieties of ferrichromes and ferrioxamines are known and well characterized.
Problems with the use of DFB, however, have resulted in the development of many projects directed to synthesis and evaluation of new iron chelators based on hydroxamic acids and other iron chelating groups. One particular class of iron chelators that appears to be a promising candidate for medical use in the treatment of Cooley's Anemia is a series of water soluble acrylic polymers which bear side chains terminated in hydroxamic acids. The length of the side chains are adjusted to optimize the fit of three neighboring hydroxamic acids about a single iron atom. Such placement retards intermolecular complexation, prevents cross-linking, and ensures that the complexes will be water soluble and, thus, capable of diffusing out of the circulatory system.
Cooley's Anemia is a genetic disorder, rare in the United States, but widely distributed throughout the Mediterranean area, the Middle East, India, and Southeast Asia. The disease, appearing largely in persons with Greek, Italian, or Oriental decent, is characterized by an inability to synthesize adequate amounts of the .beta.-chain of hemoglobin. Since excess .alpha.-chains cannot form soluble tetramers, precipitation occurs in the red cell precursors leading to their death and to the condition of anemia.
Because of the inability to synthesize the .beta.-chain of hemoglobin, the only effective treatment of .beta.-thalassemia is to administer blood transfusions throughout life. Such continual transfusions introduce large quantities of iron, which, if not removed, accumulate and form deposits in the liver, spleen, heart, and other vital organs. Death is usually by cardiac failure. To remove iron, the naturally occurring iron chelator, DFB is administered. DFB reduces iron levels by forming a stable soluble iron complex, which is eliminated in the urine and stool.
Iron chelation therapy has therefore become, over the past 20 years, an established method for treating other iron overload conditions as well. Iron poisoning, for example, most often arises in small children through the inadvertant ingestion of iron preparations. Before the introduction of iron chelation therapy in the early 1960's, such conditions were often fatal. Now, through the use of a powerful iron chelator, iron poisonings are treated with a great degree of success.
Although DFB therapy is effective in removing large quantities of iron rapidly, there are some drawbacks in its use. One of these is the short plasma residence time, about 30 minutes, which causes a significant reduction in the efficiency of DFB to remove iron. To counteract this rapid plasma clearance, the chelator is often administered by frequent slow subcutaneous infusion. A portable pump worn by the patient is often used to continuously administer a controlled amount of the drug. On the other hand, the pump is often psychologically unacceptable, and frequent injections throughout the day are painful and not very practical.
The present design of the new iron chelators has been directed largely toward mimicking the naturally occurring siderophores, such as desferrioxamine and ferrichrome, by inclusion of hydroxamic acids into a variety of structures in order to produce compounds having exceptionally high stability constants for iron, close to, or higher than that or DFB.
Besides an affinity for iron, several other criteria are required for an iron chelator to be considered for use in iron chelation therapy; high selectivity for iron, good water solubility of both the chelator and its iron complex, ability of the chelator to remove iron in vivo, and low toxicity.
A frequent approach to the development of iron chelators for medical applications, is to synthesize a series of polymers based on hydroxamic acids (HA). Hydroxamic acids are chosen as the functional group most likely to prove medically successful because of the long and extensive clinical use of DFB. The polymer would serve as a framework to hold the hydroxamic acids in close proximity to another, a feature designed to promote chelation and to ensure high stability constants of the iron complexes. It is also believed that perhaps the polymeric nature of these materials would extend the lifetime of the chelator in the plasma and thus improve chelator efficiency for iron removal.
Although several polymeric compounds with side chains terminating in hydroxamic acids have been synthesized and, to varying extents, have been shown to successfully mimick the iron chelating behavior of the naturally occuring ferroxamines, the novel iron chelating compounds of the present invention surprisingly exhibit improved stability and increased bioactivity relative to compounds presently known.